SUMMARY The number of children diagnosed with attention deficit hyperactivity disorder (ADHD) has risen steadily, yet preventable causes of ADHD remain largely unknown. Prenatal exposures to environmental chemicals, including flame retardants such as polybrominated diphenyl ethers (PBDEs), have been increasingly linked to ADHD, but their role in ADHD causation is controversial. Due to concerns about possible toxicity, manufacturers have substituted PBDEs with newer chemicals, such as halogenated non-PBDE compounds, that have not yet been investigated in human studies and thus could be even more threatening. The EPA Report on Children and the Environment identified the possible link between flame retardants and ADHD as a critical research gap that, if not promptly addressed, could keep millions of children needlessly exposed to chemicals with possible long-lasting adverse effects. We will address this urgent priority by combining behavioral assessments with state-of-the-art brain imaging?i.e., task-based functional MRI (fMRI), resting- state fMRI, and diffusion MRI?to identify the influences of flame retardants on the functioning and organization (i.e., connectivity) of children?s brains. This approach provides a significant advantage over previous studies of flame retardants, which used only behavioral ADHD assessments or clinical diagnosis and may have failed to detect preclinical alterations, underestimated effects, and provided scant neurobiological understanding. We focus on pregnancy as a critical exposure window when toxicants are most likely to affect the developing brain. However, we will also build upon new evidence demonstrating that the gut microbiome?a possible biological target of flame retardants?modulates attention and impulsivity during childhood. Hence, we will also explore whether exposures to flame retardants between 6-9 years of age?when ADHD most commonly presents? adversely affect brain function and phenotypes by altering the child?s gut microbiome. To do so, we will leverage the existing GESTE birth cohort, designed specifically to investigate flame retardant neurotoxicity in children. GESTE has extensive prenatal and childhood exposure data and neuropsychological assessments at 6-7 years. We will reevaluate children (n=500) at 8-9 years, when the proposed MRI techniques are feasible and more accurate testing for attention/impulsivity can be conducted. In Aim 1, we will determine whether prenatal exposure to PBDE flame retardants is associated with MRI abnormalities in brain function and connectivity and with ADHD behaviors and diagnosis. In Aim 2, we will determine whether prenatal exposure to halogenated non-PBDE flame retardants is associated with MRI abnormalities in brain function and connectivity and with ADHD behaviors and diagnosis. In Exploratory Aim 3, we will explore whether the levels of PBDEs and their substitutes, measured in both blood and stools during childhood, are associated with MRI brain measures, neurobehaviors and ADHD diagnosis via alterations of the gut microbiome. Our results will help identify adverse chemical effects and protect millions of children in the U.S. and worldwide.